PROJECT SUMMARY Statins are the only lipid lowering agents consistently shown to reduce the risk of death from cardiovascular disease as a monotherapy. Currently, it is estimated that greater than 39.2 million adults in the United States are on statins, and new may further increase the number of users in the U.S. alone to 56.0 million. This underscores the importance of understanding the genetic basis of statin responsiveness as well as adverse events. Statins act primarily in the liver by inhibiting 3-hydroxy-3-methylglutaryl Coenzyme A reductase (Hmgcr), the rate-limiting enzyme in the mevalonate pathway. In addition to cholesterol, the mevalonate pathway also produces other essential molecules including: isopentenyl tRNA, heme A, ubiquinone, dolichol, farnesylated and geranylgeranylated proteins, and vitamin K2. Despite over three decades of research, development, and clinical experience with statins, many unanswered questions remain about the physiological role and regulation of the mevalonate pathway in the liver. Critical gaps in knowledge include: 1) which nonsterol metabolites are most sensitive to depletion, 2) the necessity of the different mevalonate-derived metabolites for hepatocyte function, 3) the precise identity of nonsterol regulatory molecules, 4) genetic factors that determine individual variation in LDL-C lowering, and 5) the mechanisms by which statins increase the risk of type II diabetes. Our long-term goal is understand the physiological mechanisms controlling the mevalonate pathway and statin responsiveness, in order to enable personalized medicine and identify new drug targets. We propose three Specific Aims: 1) Define which isoprenoid products are required for hepatocyte viability in vivo, 2) Test the hypothesis that loss of dolichol is responsible for ER stress-induced apoptosis during potent Hmgcr inhibition, 3) Determine the physiological effects of statins on human hepatocytes in vivo. Successful completion of these studies will define the essential mevalonate-derived metabolites in the liver, and improve our understanding of new genes and pathways underlying statin-related hepatotoxicity and statin responsiveness.